Patent application WO 00/38675 discloses disubstituted maleimide compounds of Formula compounds as GSK-3 (glycogen synthase kinase-3) inhibitors of Formula (A), (B) and (C):
wherein, for Formula (A), R is hydrogen; R2 is hydrogen, 5-O-n-Pr, 5-Ph, 5-CO2Me or 5-NO2; R3 is Me or (CH2)3OH, and; R4 is Me, n-Pr, —(CH2)3X, wherein X is selected from CN, NH2, CO2H, CONH2 or OH; and, wherein, for Formula (B), R is hydrogen; R2 is hydrogen; R3 is Me or a group —(CH2)3Y, wherein Y is NH2 or OH; and, R4 is 2-Cl or 2,4-di-Cl.
Patent application WO 00/21927 describes 3-amino-4-arymaleimide compounds of Formula (I):
or a pharmaceutically acceptable derivative thereof, wherein: R is hydrogen, alkyl, aryl or aralkyl; R1 is hydrogen, alkyl, aralkyl, hydroxyalkyl or alkoxyalkyl; R2 is substituted or unsubstituted aryl or substituted or unsubstituted heterocyclyl; R3 is hydrogen, substituted or unsubstituted alkyl, cycloalkyl, alkoxyalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl or aralkyl wherein the aryl moiety is substituted or unsubstituted; or, R1 and R3 together with the nitrogen to which they are attached form a single or fused, optionally substituted, saturated or unsaturated heterocyclic ring and a method for the treatment of conditions associated with a need for inhibition of GSK-3, such as diabetes, dementias such as Alzheimer's disease and manic depression.
U.S. Pat. No. 5,057,614 to Davis, et. al., describes substituted pyrrole compounds of formula (I):
wherein R1 signifies hydrogen, alkyl, aryl (limited to phenyl), aralkyl (limited to phenylalkyl), alkoxyalkyl, hydroxyalkyl, haloalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, trialkylaminoalkyl, aminoalkylaminoalkyl, azidoalkyl, acylaminoalkyl, acylthioalkyl, alkylsulphonylaminoalkyl, arylsulphonylaminoalkyl, mercaptoalkyl, alkylthioalkyl, alkylsulphinylalkyl, alkylsulphonylalkyl, alkylsulphonyloxyalkyl, alkylcarbonyloxyalkyl, cyanoalkyl, amidinoalkyl, isothiocyanatoalkyl, glucopyranosyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, hydroxyalkylthioalkyl, mercaptoalkylthioalkyl, arylthioalkyl or carboxyalkylthioalkyl or a group of the formula—(CH2)n—W-Het (a), —(CH2)n-T-C(═V)-Z (b),—(CH2)n—NH—C(═O)-Im (c), or —(CH2)n—NH—C(═NH)—Ar (d)in which Het signifies a heterocyclyl group, W signifies NH, S or a bond, T signifies NH or S, V signifies O, S, NH, NNO2, NCN or CHNO2, Z signifies alkylthio, amino, monoalkylamino or dialkylamino, Im signifies 1-imidazolyl, Ar signifies aryl, and n stands for 2–6; R2 signifies hydrogen, alkyl, aralkyl, alkoxyalkyl, hydroxyalkyl, haloalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, acylaminoalkyl, alkylsulphonylaminoalkyl, arylsulphonylaminoalkyl, mercaptoalkyl, alkylthioalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, alkylthio or alkylsulphinyl; R3 signifies a carbocyclic or heterocyclic aromatic group; R4, R5, R6 and R7 each independently signify hydrogen, halogen, hydroxy, alkoxy, aryloxy, haloalkyl, nitro, amino, acylamino, monoalkylamino, dialkylamino, alkylthio, alkylsulphinyl or alkylsulphonyl; and one of X and Y signifies O and the other signifies O, S, (H,OH) or (H,H); with the proviso that R1 has a significance different from hydrogen when R2 signifies hydrogen, R3 signifies 3-indolyl or 6-hydroxy-3-indolyl, R4, R5 and R7 each signify hydrogen, R6 signifies hydrogen or hydroxy and X and Y both signify O and when R2 signifies hydrogen, R3 signifies 3-indolyl, R4, R5, R6 and R7 each signify hydrogen, X signifies (H,H) and Y signifies O; as well as pharmaceutically acceptable salts of acidic compounds of formula I with bases and of basic compounds of formula I with acids, as protein kinase C inhibitors and as therapeutically active substances for the use in control or prevention of inflammatory, immunological, bronchopulmonary and cardiovascular disorders.
An associated published paper (Davis, et. al., J. Med. Chem. 1992, 35, 177–184), disclosed a compound of formula (I) wherein R4, R5, R6 and R7 signify hydrogen; R1 signifies methyl; X and Y signify O; and R3 signifies 3-(7-aza-1-methylindolyl) as a protein kinase C inhibitor (IC50=2.9 μM).
Patent application WO 95/07910 describes heterocyclylindole derivatives of formula (I):
as antiviral agents. Preparation of compounds of formula (I) include use of indolyl(7-azaindolyl)maleimide compounds and bis(7-azaindolyl)maleimide compounds as reaction intermediates.
The substituted pyrroline compounds of the present invention have not been heretofore disclosed.
Accordingly, it is an object of the present invention to provide substituted pyrroline compounds useful as a kinase or dual-kinase inhibitor (in particular, a kinase selected from protein kinase C or glycogen synthase kinase-3; and, more particularly, a kinase selected from protein kinase C α, protein kinase C β-II, protein kinase C γ or glycogen synthase kinase-3β), methods for their production and methods for treating or ameliorating a kinase or dual-kinase mediated disorder.